The Clinical Genetics Branch (CGB) is NCIs base for intramural clinical cancer genetics translational research activity. CGB brings a multidisciplinary, epidemiologic perspective to: Understanding the role of genes in the cause, treatment, and prevention of cancer;Developing comprehensive management strategies for high-risk individuals and families;and Training the next generation of clinical cancer genetics investigators.<BR;BR;B>Hereditary Breast/Ovarian Cancer (HBOC) [CAS 8040]</B>comprises a genetic disease paradigm for addressing vital translational research questions. Our prospective cohort of 32 <i>BRCA</i>mutation-positive families with extensive clinical/epidemiologic data and biological samples [<b>NCI Protocol #02-C-0212</b>] has been supplemented by 133 new mutation-positive families from CGBs Breast Imaging study. Research highlights include documenting a 62% breast cancer risk reduction post risk-reducing salpingo-oophorectomy in <i>BRCA1</i>-positive families, a series of important positive, and definitive-negative candidate gene studies analyzing genetic modifiers of <i>BRCA1/2</i>-related breast cancer risk as part of the Consortium of Investigators of Modifiers of <i>BRCA1</i>(CIMBA) project, and a series of counseling/psychosocial reports of our early experience with HBOC families undergoing genetic risk assessment. The most noteworthy CIMBA-related findings include confirmation that <i>RAD51</i>significantly modifies the risk of <i>BRCA2</i>-related breast cancer, and that <i>FGFR2</i>and <i>TNRC9</i>play important roles in the risk of <i>BRCA</i>-related breast cancer. Several additional single nucleotide polymorphisms (SNP) have been evaluated in the CIMBA cohort with results reported in 2 recently published articles and 3 manuscripts currently undergoing peer review. Despite the fact that these SNPs were selected based on previous findings of strong GWAS association with breast cancer in either the general population or small cohorts of BRCA mutation carriers, most of these SNPs (rs744154 in intron 1 of <i>ERCC4</i>, Leu33Pro in <i>ITGB3</i>, rs13281615 at 8q24, and 309T to G in <i>MDM2</i>) did not show any association with breast cancer risk among BRCA mutation carriers when evaluated in CIMBAs large cohort. However, a few positive findings were identified. We observed a 12% increase in breast cancer risk associated with the minor allele for rs3817198 in <i>LSP1</i>(HR =1.16, 95%CI:1.07-1.25, p-trend=2.8x10-4) among <i>BRCA2</i>mutation carriers. There was also an increase in breast cancer risk associated with rs13387042 at 2q35 among both <i>BRCA1</i>and <i>BRCA2</i>mutation carriers (<i>BRCA1</i>: HR=1.14, 95% CI:1.04-1.25, p=.0047;<i>BRCA2</i>: HR=1.18 95%CI:1.04-1.33, p=.0079). With a mean prospective follow-up of 17.7 years for 395 mutation-negative family members, we observed no excess breast cancer risk compared with the general population. Development effots aimed at <i>in vivo</i>collection of human ovarian surface epithelial cells for translational research purposes is ongoing <b>[CAS 10376].</b><BR;BR;B>Inherited Bone Marrow Failure Syndromes (IBMFS) Study [CAS 7130]</B>targets Fanconi anemia (FA) and related disorders, which all share a predilection for aplastic anemia, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and selected solid tumors. This is the first epidemiologically-grounded, etiologically-focused investigation of these rare disorders [<B>NCI Protocol #02-C-0054</B>]. To date, 1,220 consented members from 274 families have been enrolled. Major findings to date include quantitative estimates of FA- and dyskeratosis congenita(DC)-related cancer risks, identifying the striking similarity in cancer risks in these 2 disorders (findings based on a comprehensive analysis of the first 6 years of research conducted under this protocol, submitted for publication), developing a model based on clinical phenotype which predicts the risk of critical FA outcomes (marrow failure, transplant, cancer and death), expanding the clinical phenotype of these disorders and identifying very short telomeres as pathognomonic for DC. We have received a grant from the Fanconi Anemia Research Foundation to study <i>in vitro</i>immune function in FA patients <b>[CAS 10475].</b>We have completed collaborative analyses of cancer risks in the German (published) and Israeli (submitted) FA cohorts. The results were concordant with those previously-reported in our North American FA study. In collaboration with sub-specialty colleagues, we have reported abnormal ear and eye findings in FA and DC.<BR;BR;b>Familial Testicular Cancer [CAS 7070, 7130]</b>is an inadequately-studied familial cancer disorder being evaluated under 2 protocols, one accruing new multiple-case families [<b>NCI Protocol #02-C-0178</b>], the other aimed at mapping and cloning new TGCT susceptibility genes [<b>NCI Protocol #04-C-N076</b>]. Through the former, we have enrolled 609 consented members from 119 newly-ascertained families. Findings from this multidisciplinary, etiologically-oriented family study include finding that testicular microlithiasis is more common than expected in TGCT kindred, recognition of a possible new FTGCT syndrome characterized by renal and pituitary neoplasms, colonic polyps, lipomas and lentigenes, and identifying germline mutations in the <i>PDE11A</i>gene as modifier of FTGCT risk. We are the second largest contributor to International Testicular Cancer Linkage Consortium, through which we have published a descriptive analysis of 469 TGCT families (containing 1002 TGCT cases), and documented that age-at-cancer-diagnosis is significantly younger in familial versus sporadic TGCT. <BR;BR>We have initiated a new study of the <b>Li-Fraumeni Syndrome (LFS) [CAS 10503]</b>is a rare, inherited disorder caused by germline <i>TP53</i>mutations, with increased risks of early-onset bone and soft tissue sarcomas, breast, adrenal and brain cancer. We will conduct comprehensive clinical evaluations, provide genetic counseling and testing, investigate cancer screening modalities, identify genetic modifiers, study cancer risk-reduction strategies, and search for the genetic etiology in the 30% of affected patients without a <i>TP53</i>mutation. <BR;BR><b>Genetic Counseling, Psychosocial and Behavioral Studies in Familial Cancer</b>is a vital component of CGBs research portfolio, which has yielded more than 30 peer-reviewed publications. A series of projects are actively underway as part of each familial cancer study being conducted by the Branch. We are developing new genetic counseling tools (<i>e.g.,</i>the Colored Ecogenetics Relationship Map), applying novel analytic strategies, such as social network analysis, analyzing the variables associated with choosing surgery or screening in GOG-199, assessing determinants of bone marrow transplant decision-making within FA families, and exploring the impact of ambiguous screening test results on mood and screening behavior of <i>BRCA1/2</i>mutation carriers.